In order to exploit the potential of focused ultrasound therapy, high-power phased array transducers with large number of elements are required. Current methods have two major drawbacks. First, the electrical impedance of individual array elements becomes large as their size is reduced. Second, arrays are not able to deliver adequate acoustic power for some advanced applications. We have discovered a method to overcome both of these limitations and propose to develop new phased array technology for therapeutic ultrasound based on this approach. More specifically in this proposal we will develop a system based on this technology for the treatment of stroke. Despite millions of dollars spent on acute stroke intervention trials over the last decade, only strategies that open blocked arteries and reperfuse ischemic penumbra within 3-6 hours of onset have proven to be effective. Clinical studies have shown that transcranial ultrasound and Doppler ultrasound can significantly increase the number of patients that will have recanalization of the occluded vessel when administrated together with tissue plasminogen activator (tPA). However, there are still a large number of patients whose arterial occlusion is not resolved with the current use of Doppler ultrasound exposure. It is our hypothesis that transcranial sonication using phased array applicators and patient-specific skull information derived from CT scans can better localize ultrasound energy within the brain, and that this will result in further improvements in patient response as compared with existing approaches. Precise localization of ultrasound energy within the brain could also enable the use of ultrasound alone without a thrombolytic agent thus eliminating the potential side effects of these substances. The specific tasks to be completed during this grant period are: First, development of the new array technology, second, development of an ultrasound system for the treatment of stroke, third, measurements of skull properties at the required frequency range, and fourth, tests of the complete system with ex vivo human skulls. In addition we will determine the optimal ultrasound exposures for the stroke treatments with and without tPA using ex vivo and in vivo models. Finally, we will test the short and long term impact of the treatments in two different animal models. At the end of this research we will have developed a phased array technology that can overcome the remaining barriers in applying this technology optimally for ultrasound therapy. In addition we will have completed a prototype system and will have conducted pre-requisite preclinical testing to be in a position for subsequent clinical trials for the treatment of acute stroke. Public Health Relevance Statement (provided by applicant): Despite millions of dollars spent on acute stroke intervention trials over the last decade, only strategies that open blocked arteries and reperfuse ischemic penumbra within 3-6 hours of onset have proven to be effective. Only a few percent of all stroke patients receive clot-busting treatments, however, due to the system requirements to deliver appropriate care. It is our hypothesis that a larger number of patients could benefit from these treatments if advanced phased array systems are used to accelerate thrombolysis. The phased arrays would allow predictable ultrasound exposures and minimize impact on the surrounding tissues. During this research we plan to develop such a system and perform all of the experiments needed prior to starting clinical trials. This research may have a major impact on patient care.